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Clinical Trials: Immunotherapy

Phase I Clinical Trial of Combination Propranolol and Pembrolizumab in Locally Advanced and Metastatic Melanoma: Safety, Tolerability, and Preliminary Evidence of Antitumor Activity

Shipra Gandhi, Manu R. Pandey, Kristopher Attwood, Wenyan Ji, Agnieszka K. Witkiewicz, Erik S. Knudsen, Cheryl Allen, Joseph D. Tario, Paul K. Wallace, Carlos D. Cedeno, Maria Levis, Suzanne Stack, Pauline Funchain, Joseph J. Drabick, Mark J. Bucsek, Igor Puzanov, Hemn Mohammadpour, Elizabeth A. Repasky and Marc S. Ernstoff
Shipra Gandhi
1Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York.
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  • For correspondence: shipra.gandhi@roswellpark.org
Manu R. Pandey
1Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York.
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Kristopher Attwood
2Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, New York.
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Wenyan Ji
2Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, New York.
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Agnieszka K. Witkiewicz
3Center for Personalized Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York.
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Erik S. Knudsen
3Center for Personalized Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York.
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  • ORCID record for Erik S. Knudsen
Cheryl Allen
1Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York.
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Joseph D. Tario
4Department of Flow Cytometry, Roswell Park Comprehensive Cancer Center, Buffalo, New York.
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Paul K. Wallace
4Department of Flow Cytometry, Roswell Park Comprehensive Cancer Center, Buffalo, New York.
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Carlos D. Cedeno
4Department of Flow Cytometry, Roswell Park Comprehensive Cancer Center, Buffalo, New York.
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Maria Levis
5Clinical Research Service, Roswell Park Comprehensive Cancer Center, Buffalo, New York.
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Suzanne Stack
5Clinical Research Service, Roswell Park Comprehensive Cancer Center, Buffalo, New York.
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Pauline Funchain
6Department of Hematology and Medical Oncology, Cleveland Clinic, Cleveland, Ohio.
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Joseph J. Drabick
7Division of Hematology and Oncology, Penn State Cancer Institute, Hershey, Pennsylvania.
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Mark J. Bucsek
8Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, New York.
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Igor Puzanov
1Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York.
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Hemn Mohammadpour
8Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, New York.
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Elizabeth A. Repasky
8Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, New York.
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Marc S. Ernstoff
1Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York.
9Division of Cancer Treatment and Diagnosis/Developmental Therapy Program-ImmunoOncology Branch, NIH/NCI, Bethesda, Maryland.
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DOI: 10.1158/1078-0432.CCR-20-2381 Published January 2021
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Abstract

Purpose: Increased β-adrenergic receptor (β-AR) signaling has been shown to promote the creation of an immunosuppressive tumor microenvironment (TME). Preclinical studies have shown that abrogation of this signaling pathway, particularly β2-AR, provides a more favorable TME that enhances the activity of anti–PD-1 checkpoint inhibitors. We hypothesize that blocking stress-related immunosuppressive pathways would improve tumor response to immune checkpoint inhibitors in patients. Here, we report the results of dose escalation of a nonselective β-blocker (propranolol) with pembrolizumab in patients with metastatic melanoma.

Patients and Methods: A 3 + 3 dose escalation study for propranolol twice a day with pembrolizumab (200 mg every 3 weeks) was completed. The primary objective was to determine the recommended phase II dose (RP2D). Additional objectives included safety, antitumor activity, and biomarker analyses. Responders were defined as patients with complete or partial response per immune-modified RECIST at 6 months.

Results: Nine patients with metastatic melanoma received increasing doses of propranolol in cohorts of 10, 20, and 30 mg twice a day. No dose-limiting toxicities were observed. Most common treatment-related adverse events (TRAEs) were rash, fatigue, and vitiligo, observed in 44% patients. One patient developed two grade ≥3 TRAEs. Objective response rate was 78%. While no significant changes in treatment-associated biomarkers were observed, an increase in IFNγ and a decrease in IL6 was noted in responders.

Conclusions: Combination of propranolol with pembrolizumab in treatment-naïve metastatic melanoma is safe and shows very promising activity. Propranolol 30 mg twice a day was selected as RP2D in addition to pembrolizumab based on safety, tolerability, and preliminary antitumor activity.

Footnotes

  • Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).

  • Clin Cancer Res 2021;27:87–95

  • Received June 18, 2020.
  • Revision received September 9, 2020.
  • Accepted October 21, 2020.
  • Published first October 30, 2020.
  • ©2020 American Association for Cancer Research.
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Clinical Cancer Research: 27 (1)
January 2021
Volume 27, Issue 1
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Phase I Clinical Trial of Combination Propranolol and Pembrolizumab in Locally Advanced and Metastatic Melanoma: Safety, Tolerability, and Preliminary Evidence of Antitumor Activity
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Phase I Clinical Trial of Combination Propranolol and Pembrolizumab in Locally Advanced and Metastatic Melanoma: Safety, Tolerability, and Preliminary Evidence of Antitumor Activity
Shipra Gandhi, Manu R. Pandey, Kristopher Attwood, Wenyan Ji, Agnieszka K. Witkiewicz, Erik S. Knudsen, Cheryl Allen, Joseph D. Tario, Paul K. Wallace, Carlos D. Cedeno, Maria Levis, Suzanne Stack, Pauline Funchain, Joseph J. Drabick, Mark J. Bucsek, Igor Puzanov, Hemn Mohammadpour, Elizabeth A. Repasky and Marc S. Ernstoff
Clin Cancer Res January 1 2021 (27) (1) 87-95; DOI: 10.1158/1078-0432.CCR-20-2381

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Phase I Clinical Trial of Combination Propranolol and Pembrolizumab in Locally Advanced and Metastatic Melanoma: Safety, Tolerability, and Preliminary Evidence of Antitumor Activity
Shipra Gandhi, Manu R. Pandey, Kristopher Attwood, Wenyan Ji, Agnieszka K. Witkiewicz, Erik S. Knudsen, Cheryl Allen, Joseph D. Tario, Paul K. Wallace, Carlos D. Cedeno, Maria Levis, Suzanne Stack, Pauline Funchain, Joseph J. Drabick, Mark J. Bucsek, Igor Puzanov, Hemn Mohammadpour, Elizabeth A. Repasky and Marc S. Ernstoff
Clin Cancer Res January 1 2021 (27) (1) 87-95; DOI: 10.1158/1078-0432.CCR-20-2381
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